Download Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study

Dual bronchodilation with QVA149 versus single bronchodilator therapy: the
SHINE study
Eric Bateman*, Gary T Ferguson#, Neil Barnes¶, Nicola Gallagher†, Yulia Green†, Michelle
Henley†, Donald Banerji§
*Department of Medicine, University of Cape Town, Cape Town, South Africa
#
Pulmonary Research Institute of Southeast Michigan, Livonia, Michigan, USA
¶
London Chest Hospital, Barts Health NHS Trust, London, UK
†
Novartis Horsham Research Centre, Horsham, UK
§
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
1
METHODS (ADDITIONAL DETAILS)
Study design
The study was conducted in academic and clinical research centres in Europe, North
America, South America, Asia (Philippines, Japan, India), Australia, China, Taiwan and
South Africa.
During washout, patients discontinued long-acting bronchodilator therapy: at least seven days
for long-acting muscarinic antagonists and the long-acting β2-agonist (LABA) indacaterol,
and 48 hours for all other LABAs and LABA/inhaled corticosteroid (ICS) combinations.
Concomitant medications permitted during the SHINE study are detailed in appendix table 2.
Screening tests were performed and baseline electronic diary data collected during a 14-day
run-in period.
Randomisation and blinding
Eligible patients were assigned a randomisation number via Interactive Response Technology
(IRT), linking the patient to a treatment arm and specific unique medication number for the
study drug. The randomisation number was not communicated to the investigator contacting
the IRT. Patients randomised to open-label tiotropium were not assigned a medication
number as this treatment was supplied locally. Randomisation was stratified by baseline
smoking status and ICS use.
Blinding of patients, investigator staff, personnel performing assessments and data analysts
was maintained by ensuring randomisation data remained strictly confidential and
inaccessible to anyone involved in the study until the time of unblinding. In addition, the
identity of the treatments was concealed by the use of study drugs that were all identical in
packaging, labelling, and schedule of administration, appearance, taste and odour. Unblinding
occurred in the case of emergencies and at the conclusion of the study. The bioanalyst of the
pharmacokinetic samples was unblinded.
Statistical methods
Statistical power
For the primary endpoint, 1710 evaluable patients gave 87% power for QVA149 versus the
mono-components, >99% power for active drugs versus placebo, and 80% power for noninferiority of QVA149 versus tiotropium. A standard deviation of 245 mL was assumed for
trough forced expiratory volume in 1 second (FEV1) and a treatment difference in trough
FEV1 of 120 mL (minimally clinically important difference [MCID]) was assumed for active
versus placebo, 60 mL (1/2 MCID) for QVA149 versus the mono-components and a noninferiority margin of 40 mL (1/3 MCID) for QVA149 versus tiotropium. This sample size
also gave adequate power for the three key secondary endpoints (Transition Dyspnoea Index
[TDI] focal score, 92%; St George’s Respiratory Questionnaire [SGRQ] total score, 81%;
rescue medication use, >99%).
Statistical analyses
Efficacy analyses were conducted on all randomised patients who received at least one dose
of study drug (full analysis set [FAS]) according to treatment assignment at randomisation.
The safety set comprised all patients receiving at least one dose of study drug; patients were
analysed according to the treatment they received.
2
The primary variable of trough FEV1 at Week 26 (with missing values imputed with last
observation carried forward [LOCF]) was analysed for the FAS using a mixed model with
treatment as a fixed effect and covariates of baseline FEV1, FEV1 before and after salbutamol
and ipratropium inhalation. The model also included baseline smoking status (current/exsmoker), baseline ICS use (yes/no) and region as fixed effects with centre nested within
region as a random effect. Estimated treatment differences are presented as least squares
means (LSM) with standard errors, and associated 95% confidence intervals (CI). Superiority
of QVA149 versus indacaterol or glycopyrronium was demonstrated if the adjusted one-sided
p-value was less than the multiplicity adjusted significance level. Key and important
secondary efficacy variables were analysed using the same method as for the analysis of the
primary variable, with Baseline Dyspnoea Index, baseline SGRQ or baseline rescue
medication use replacing the baseline FEV1 covariate as appropriate. Superiority of QVA149
and other active treatments versus placebo, and non-inferiority of QVA149 versus tiotropium
(for trough FEV1) was demonstrated if the adjusted one-sided p-value was less than the
multiplicity adjusted significance level. Non-inferiority of QVA149 versus tiotropium was
evaluated for the per-protocol set (non-inferiority criterion, 40 mL treatment difference); all
other treatment comparisons were evaluated for the FAS. Other secondary efficacy variables
were analysed using similar methods, with appropriate baseline measurements as covariates
and no adjustment for multiplicity was made. For the responder analyses of dyspnoea and
health status performed using logistic regression, the estimated adjusted odds ratios are
displayed along with the associated 95% CIs and two-sided p-values. Analyses of trough
FEV1 at Week 26 performed in subgroups divided according to age, gender, disease severity,
and ICS use, included appropriate interaction terms and additional covariates as appropriate
in the analysis model, and no adjustment for multiplicity was made. Adverse events and other
safety endpoints are presented using descriptive statistics.
RESULTS (ADDITIONAL DETAILS)
Spirometry
Increase from baseline in trough FEV1 at Week 26
All active treatments at Week 26 (LOCF) had an increase from baseline in trough FEV1, the
mean increase being highest for the QVA149 group (0.16 L, +15.3%); mean change from
baseline for indacaterol was 0.08 L (+7.7%); glycopyrronium 0.07 L (+7.1%), and tiotropium
0.09 L (+9.3%).
Post-hoc analyses of the primary endpoint
Post-hoc analyses indicated that the proportion of patients with an increase of >100 mL in
trough FEV1 at Week 26 (LOCF) from baseline was greater for QVA149 (64.3%) compared
with indacaterol (46.2%), glycopyrronium (43.2%), tiotropium (46.6%) and placebo (18.9%),
(p<0.001 for all treatment comparisons). The proportion of patients with an increase of
>200mL from baseline in trough FEV1 at Week 26 (LOCF) from baseline was greater for
QVA149 (39.8%) compared with indacaterol (26.2%), glycopyrronium (23.8%), tiotropium
(25.1%) and placebo (8.4%), (p<0.001 for all treatment comparisons).
Secondary analyses
FEV1 area under the curve [AUC]0–12 h was significantly greater in the QVA149 treatment
group compared with placebo and the active comparators at Day 1 (all p<0.001; table 2). At
Week 26, QVA149 provided significant improvements versus placebo and the active
comparators in FEV1 AUC0–24 h (all p<0.001) and FEV1 AUC12–24 h (all p<0.01; table 2).
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QVA149 demonstrated a statistically significant improvement in FEV1 2 hours post-dose
compared with placebo and all active comparators at Week 26 (p<0.001; table 2).
Inspiratory capacity was statistically significantly greater in the QVA149 treatment group
than in the placebo group at all assessed time points including Day 1 (LSM treatment
difference: 0.18 L–0.28 L), Week 12 (LSM treatment difference: 0.24 L–0.32 L) and Week
26 (LSM treatment difference: 0.16 L–0.31 L).
Trough forced vital capacity (FVC) was significantly greater in the QVA149 group at Day 1,
Week 12 and Week 26 compared with placebo, indacaterol, glycopyrronium and tiotropium
groups (all p<0.001; appendix figure 2). Improvements in FVC were statistically significantly
greater with QVA149 versus placebo at all assessed timepoints on Day 1 and at Weeks 12
and 26 (all p<0.001).
Pre-planned subgroup analyses
Additional analyses of trough FEV1 at Week 26 demonstrated that data for the subgroups of
age, gender, severity of chronic obstructive pulmonary disease (COPD) and baseline ICS use
were similar to those of the overall population (appendix figure 3).
Dyspnoea
The proportion of patients achieving a minimal clinically important difference for TDI score
(improvement of ≥1 point [1]) at Week 26 was significantly greater in the QVA149 group
(68.1%) compared with placebo (57.5%; p=0.004) and tiotropium groups (59.2%; p=0.016;
appendix figure 5). Significantly greater proportions of patients receiving QVA149 achieved
improvements in TDI score of ≥2 points (p=0.004) and ≥3 points (p=0.019) compared with
placebo at Week 26 (appendix figure 5). More than half (56.7%) of the QVA149 patients had
major improvements (≥3 points) in TDI focal score (appendix table 4).
Health status
An improvement in SGRQ total score was seen at Week 12 with QVA149 compared with
placebo (LSM difference: –3.99; p<0.001), glycopyrronium (LSM difference: –1.84;
p=0.020) and tiotropium (LSM difference: –2.37; p=0.003). The proportion of patients
achieving the MCID for SGRQ total score (≥4-point reduction [2]) at Week 26 was
significantly greater in patients receiving QVA149 compared with those receiving tiotropium
(p=0.047 [appendix table 5; appendix figure 5]). Additionally, significantly greater
proportions of patients receiving QVA149 or indacaterol achieved improvements in SGRQ
total score of ≥8 compared with placebo, glycopyrronium and tiotropium at Week 26 (p<0.05
[appendix table 5; appendix figure 5]).
REFERENCES
1. Witek TJ, Jr., Mahler DA. Minimal important difference of the transition dyspnoea
index in a multinational clinical trial. Eur Resp J 2003; 21: 267–272.
2. Jones P, Lareau S, Mahler DA. Measuring the effects of COPD on the patient. Respir
Med 2005; 99: Suppl. B, S11–S18.
4
TABLE S1. Inclusion and exclusion criteria – the SHINE study
Inclusion criteria
•
•
•
•
•
•
Male or female adults aged ≥40 years, who had signed an Informed Consent Form
prior to initiation of any study-related procedure.
Patients with moderate-to-severe stable COPD (Stage II or Stage III) according to the
GOLD Guidelines 2008.
Current or ex-smokers who had a smoking history of at least 10 pack-years (defined
as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years etc.).
Patients with a post-bronchodilator FEV1 ≥30% and < 80% of the predicted normal,
and post-bronchodilator FEV1/FVC < 0.7 at Visit 2 (Day 14).
Post refers to 1 hour after sequential inhalation of 84 μg (or equivalent dose) of
ipratropium bromide and 400 μg of salbutamol.
Symptomatic patients, according to daily electronic diary data between Visit 2 (Day
14) and Visit 3 (Day 1), with a total score of 1 or more on at least 4 of the last 7 days
prior to Visit 3 (the main study diary was used).
Exclusion criteria
General exclusion
•
•
•
•
•
•
•
•
•
•
Pregnant women or nursing mothers (pregnancy confirmed by positive urine
pregnancy test).
Women of child-bearing potential.
Patients contraindicated for treatment with, or having a history of
reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar
class or any component thereof:
• anticholinergic agents
• long and short acting β2-agonists
• sympathomimetic amines
• lactose or any of the other excipients.
Patients with a history of long QT syndrome or whose corrected QT measured at
Visit 2 (Day 14) (Fridericia method) is prolonged (>450 ms for males and females) as
confirmed by the central electrocardiogram assessor.
Patients who had a clinically significant abnormality on the Visit 2 ECG who in the
judgment of the investigator were at potential risk if enrolled into the study (these
patients were not re-screened).
Patients with Type I or uncontrolled Type II diabetes.
Patients who had not achieved an acceptable spirometry result at Visit 2 in
accordance with the American Thoracic Society/European Respiratory Society
criteria for acceptability and repeatability.
Patients with narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladderneck obstruction or moderate-to-severe renal impairment or urinary retention
(patients with a transurethral resection of prostate were excluded from the study;
patients who had undergone full re-section of the prostate were considered for the
study, as well as patients who were asymptomatic and stable on pharmacological
treatment for the condition).
Patients with a history of malignancy of any organ system (including lung cancer),
treated or untreated, within the past 5 years whether or not there is evidence of local
recurrence or metastases, with the exception of localised basal cell carcinoma of the
skin.
Patients who, in the judgment of the investigator, had a clinically relevant laboratory
abnormality or a clinically significant condition such as (but not limited to):
• unstable ischemic heart disease, left ventricular failure (New York Heart
Association Class III and IV), history of myocardial infarction, arrhythmia
(excluding chronic stable atrial fibrillation). Patients with such events not
5
•
•
considered clinically significant by the investigator were considered for
inclusion in the study
• uncontrolled hypo-or hyperthyroidism, hypokalemia or hyperadrenergic state
any condition which might compromise patient safety or compliance, interfere
with evaluation, or preclude completion of the study.
Patients unable to use an electronic patient diary.
Patients who were, in the opinion of the investigator unreliable or non-compliant.
COPD specific exclusion
•
•
•
•
•
•
•
•
•
•
Patients requiring long term oxygen therapy (>15 hours a day) on a daily basis for
chronic hypoxemia.
Patients who had a COPD exacerbation that required treatment with antibiotics,
systemic steroids (oral or intravenous) or hospitalisation in the 6 weeks prior to Visit 1
or between Visit 1 and Visit 3.
• Patients who developed a COPD exacerbation during period between Visits 1
and 3 were not eligible but were permitted to be re-screened after a minimum
of 6 weeks after the resolution of the COPD exacerbation.
Patients who had a respiratory tract infection within 4 weeks prior to Visit 1. Patients
who developed an upper or lower respiratory tract infection during the screening
period (up to Visit 3) were not eligible, but were permitted to be re-screened 4 weeks
after the resolution of the respiratory tract infection.
Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless
confirmed by chest X-ray to be no longer active) or clinically significant
bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.
Patients with lung lobectomy, lung volume reduction, or lung transplantation.
Patients with any history of asthma indicated by (but not limited to) a blood eosinophil
count >600/mm3 (at Visit 2) or onset of symptoms prior to 40 years. Patients without
asthma but who had a blood eosinophil count >600/mm3 at Visit 2 were excluded.
Patients with allergic rhinitis who used a H1 antagonist or intra-nasal corticosteroids
intermittently (treatment with a stable dose is permitted).
Patients with eczema (atopic), known high immunoglobulin E levels, or a known
positive skin prick test in the last 5 years.
Patients with known history and diagnosis of α-1 antitrypsin deficiency.
Patients who were participating in the active phase of a supervised pulmonary
rehabilitation program.
COPD: chronic obstructive pulmonary disease; ECG: electrocardiogram; FEV1: forced
expiratory volume in 1 second; FVC: forced vital capacity.
6
TABLE S2. Concomitant medication allowed in the SHINE study
Selective serotonin reuptake inhibitors prior to
Treatment regimen has been stable for at
screening
least one month prior to screening visit
and during the study. Screening ECG is
normal with no clinical evidence of prior
ECG abnormalities
Inactivated vaccine
Not administered within 48 hrs prior to a
study visit
Inhaled corticosteroids
In constant doses and dose regimens for
at least 1 month
Intranasal corticosteroids
In constant doses and dose regimens for
at least 5 days prior to screening
H1 antagonists
In constant doses and dose regimens
ECG: electrocardiogram.
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TABLE S3. Dyspnoea, health status, rescue medication use and patient symptoms over the 26-week study
QVA149 110/50 µg
Indacaterol 150 µg
Glycopyrronium 50 µg
Difference
p-valuesa Difference vs p-valuesa Difference vs p-valuesa
Placebo
vs placebo
placebo
placebo
(LSM,
(LSM ±
(LSM ± 95%
(LSM ± 95%
SE)
95% CI)
CI)
CI)
TDI focal
1.63
1.09 (0.61,
*p<0.001
0.84 (0.36,
*p<0.001
0.89 (0.41,
*p<0.001
§
score at
(0.230)
1.57)
p=0.007
1.31)
1.36)
Week 26b
SGRQ total
40.02
–3.01 (–
*p<0.002 –1.92 (–3.97,
–1.83 (–3.87,
−
−
scoreb
(0.941)
5.05, –0.97) §p=0.009
0.12)
0.21)
Rescue
–0.92
–0.96 (–
*p<0.001 –0.65 (–0.99, *p<0.001 –0.30 (–0.63,
−
‡
medication
(0.147)
1.29, –0.62) †p=0.027
–0.32)
p=0.011
0.04)
‡
use
p<0.001
§
p<0.001
Days with no 34.76
12.33 (6.84, *p<0.001
10.05 (4.55, *p<0.001 2.98 (–2.52,
−
‡
‡
rescue
(2.437)
17.82)
p<0.001
15.55)
p=0.002
8.48)
§
§
medication
p<0.001
p<0.001
use, %
Nights with
53.67
10.01 (5.37, *p<0.001
8.81 (4.16,
*p<0.001
4.97 (0.31,
*p=0.037
‡
‘no nighttime (2.047)
14.66)
p=0.008
13.47)
9.62)
awakenings’,
%
Days with
4.44
3.05 (0.14,
*p=0.040
4.73 (1.81,
*p=0.001 1.96 (–0.96,
−
‡
‘no daytime
(1.294)
5.96)
7.64)
p=0.021
4.87)
§
symptoms’,
p=0.002
%
‘Days able to 34.49
11.48 (6.52, *p<0.001
6.44 (1.47,
*p=0.011
5.61 (0.63,
*p=0.027
†
perform
(2.197)
16.44)
p=0.012
11.41)
10.58)
‡
usual daily
p=0.004
§
activities’, %
p<0.001
Tiotropium 18 µg
Difference
p-valuesa
vs placebo
(LSM ±
95% CI)
0.58 (0.10,
*p=0.017
1.06)
–0.88 (–
2.92, 1.16)
–0.41 (–
0.75, –0.08)
−
*p=0.015
1.75 (–3.73,
7.23)
−
6.33 (1.70,
10.97)
*p=0.007
1.10 (–1.81,
4.00)
−
3.03 (–1.92,
7.98)
−
8
a
p-values presented where p<0.05; bImputed with last observation carried forward; *versus placebo; other symbols denote where significant
treatment differences (not shown) occur; †versus indacaterol; ‡versus glycopyrronium; §versus tiotropium. CI: confidence interval; LSM: least
squares mean; SE: standard error; SGRQ: St George’s Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.
9
TABLE S4. Proportion of patients with minimally clinically important difference in TDI at Week 26 (LOCF, full analysis set)
Treatment
Placebo
QVA149
Indacaterol
Glycopyrronium
Tiotropium
≥1 point
(mild)
% patients
p-valuesa
57.5
−
68.1
*p=0.004
§
p=0.016
64.6
*p=0.020
63.7
*p=0.018
59.2
−
TDI improvement
≥2 points
(moderate)
% patients
p-valuesa
51.3
−
62.9
*p=0.004
§
p=0.019
59.6
*p=0.014
59.4
*p=0.005
§
p=0.024
54.2
−
≥3 points
(major)
% patients
p-valuesa
46.6
−
56.7
*p=0.019
§
p=0.019
53.6
−
53.8
*p=0.019
§
p=0.021
48.8
−
a
p-values presented where p<0.05; *versus placebo; §versus tiotropium. LOCF: last observation carried forward;
TDI: Transitional Dyspnoea Index.
10
TABLE S5. Proportion of patients with minimally clinically important difference in SGRQ
at Week 26 (LOCF, full analysis set)
Treatment
Placebo
QVA149
Indacaterol
Glycopyrronium
Tiotropium
a
SGRQ improvement
≥4 points
≥8 points
% patients
p-valuesa
% patients
p-valuesa
56.6
37.8
−
−
§
63.7
51.3
*p=0.002
p=0.047
‡
p=0.002
§
p=0.001
63.0
49.2
*p=0.006
−
‡
p=0.008
§
p=0.006
60.5
41.9
−
−
56.4
40.2
−
−
§
‡
p-values presented where p<0.05; *versus placebo; versus tiotropium; versus glycopyrronium.
LOCF: last observation carried forward; SGRQ: St George’s Respiratory Questionnaire.
11
FIGURE LEGENDS
FIGURE S1. FEV1 (L) at 5 min and 30 min after dosing (full analysis set).
***p<0.001; values are LSM ± SE; n = number per treatment group in the full analysis set.
FIGURE S2. Trough FVC (L).
p<0.001 for QVA149 versus placebo, indacaterol, glycopyrronium and tiotropium at the end
of Day 1, Weeks 12 and 26. Values are LSM ± SE; n = number per treatment group in the full
analysis set.
FIGURE S3. Subgroup analyses of trough FEV1 (L) with QVA149 versus placebo and active
treatments after 26 weeks treatment (LOCF)
a) By baseline ICS use
b) By disease severity (*moderate or less; **severe or worse)
c) By gender
d) By age
N1 = number of patients included in the analysis in the QVA149 arm of the respective
subgroup. N2 = number of patients included in the analysis in the comparator arm of the
respective subgroup.
FIGURE S4. TDI focal score at a) Week 26 (LOCF) and b) Week 12 (LOCF).
a) ***p<0.001; §p=0.017; †p=0.007; values are LSM ± SE. n = number per treatment group in the full
analysis set.
b) ***p<0.001; §p=0.012; †p=0.046; *p=0.030; values are LSM ± SE. n = number per treatment group
in the full analysis set.
FIGURE S5. Odds ratios for differences between the active treatments and placebo in the
proportion of patients achieving specified improvements in TDI and SGRQ scores at Week
26 (LOCF).
Data are presented as odds ratios ± 95% CIs. *p<0.05, **p<0.01 versus placebo. Other
symbols denote where significant differences (not shown) occur: ‡‡p<0.01 versus
glycopyrronium 50 µg; §p<0.05, §§p<0.01 versus tiotropium 18 µg. CI: confidence interval;
SGRQ: St George’s Respiratory Questionnaire; TDI: Transitional Dyspnoea Index.
FIGURE S6. Mean change from baseline in SGRQ total scorea after 26 weeks of treatment.
Negative value signifies improvement. Data presented as mean ± SE. n = number per
treatment group in the full analysis set. aImputed from last observation carried forward.
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Figure S1
13
Figure S2
14
Figure S3
a)
b)
15
c)
16
d)
17
18
Figure S4
a)
19
b)
20
Figure S5
Figure S6
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